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WO1999062537A1 - Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques - Google Patents

Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques Download PDF

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Publication number
WO1999062537A1
WO1999062537A1 PCT/US1999/012681 US9912681W WO9962537A1 WO 1999062537 A1 WO1999062537 A1 WO 1999062537A1 US 9912681 W US9912681 W US 9912681W WO 9962537 A1 WO9962537 A1 WO 9962537A1
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Prior art keywords
glycoprotein
agent
migration
tissue factor
dendritic cells
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PCT/US1999/012681
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English (en)
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WO1999062537A9 (fr
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Sylvie Beaulieu
Gwendalyn J. Randolph
William A. Muller
Ralph M. Steinman
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The Rockefeller University
The Cornell Research Foundation
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Priority to AU44237/99A priority Critical patent/AU4423799A/en
Publication of WO1999062537A1 publication Critical patent/WO1999062537A1/fr
Publication of WO1999062537A9 publication Critical patent/WO1999062537A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to methods and agents for enhancing or suppressing the development of immunity and the immune response by modulating the migration of dendritic cells, and methods for identifying agents with migration modulating activity. Methods and agents for the enhancement of monocyte migration out of chronic inflammatory foci are also provided.
  • an antigen encountered by antigen-presenting cells is taken up, processed, and its peptides subsequently prime T lymphocytes to generate antigen-specific T lymphocytes (e.g., cytotoxic and memory cells), and through the interaction with B cells, result in the formation of antigen-specific antibodies.
  • Immune responses are initiated after antigen-presenting cells, particularly dendritic cells (DC), capture antigens in organs such as skin, lung and gut, and migrate via afferent lymphatic vessels to draining lymph nodes.
  • DC dendritic cells
  • T lymphocytes continually recirculate through lymph nodes, so the newly arrived, antigen-bearing DC become positioned to select lymphocytes that bear receptors for the presented antigens (1).
  • epidermal DC also termed Langerhans cells
  • the DC undergo maturation, increasing their expression of molecules involved in antigen presentation, including major histocompatibility complex (MHC) II products, CD80 (B7-1), and CD86 (B7-2) (4, 5).
  • MHC major histocompatibility complex
  • dendritic cell migration is a critical step in both the induction of immunity and in the immune response.
  • Dendritic cell migration is essential for the successful induction of an immune response to an administered vaccine, for eliciting antibody production and cell- mediated immunity against infectious microorganisms and arising neoplastic cells within the body.
  • dendritic cell migration is responsible for diseases involving an exaggerated, inappropriate or undesired immune response such as allergic asthma, food allergies, contact dermatitis, seasonal allergies, and autoimmune diseases such as psoriasis, in which known or as-yet undescribed antigens are transported to T lymphocytes.
  • White blood cells known as monocytes are precursors of dendritic cells and tissue macrophages.
  • Blockage of or interference with dendritic cell migration interferes with the immune response. Blockage has been achieved by the use of antibodies against certain dendritic cell proteins.
  • dendritic cells Down-regulate E-cadherin, allowing retraction from neighboring keratinocytes (31).
  • epidermal DC up-regulate MHC II and retract from neighboring keratinocytes, and fail to migrate out of the epidermis (32).
  • Another adhesion molecule, CD44 is also used by DC during mobilization from the epidermis (33).
  • the inventors herein have made the surprising and unanticipated finding that certain dendritic cell membrane proteins, namely p-glycoprotein, also known as MDR-1, the transporter responsible for multi-drug resistance, and tissue factor (TF), a procoagulant protein, are involved in the migration of dendritic cells (DCs) from the peripheral tissues to the lymphatic vessels. Alteration of dendritic cell migration activity by manipulating these surface proteins is useful for both enhancing and suppressing the immune response. Furthermore, the migration of monocyte-derived cells out of tissues has been found to be inhibited by agents which interfere with monocyte p-glycoprotein.
  • agents for the modulation of immunity and the immune response in a mammal is provided by an agent which is capable of interacting with the dendritic cell membrane proteins p-glycoprotein and tissue factor, and altering the migration of dendritic cells from the peripheral tissues to the lymphatic vessels.
  • modulation results in decreasing the migration of dendritic cells and hence the suppression of immunity or of an immune response.
  • Agents useful for the practice of this aspect of the invention include antibodies and antibody fragments which bind to p- glycoprotein, agents which block transport activity of p-glycoprotein, antisense oligonucleotides to p-glycoprotein and antagonists of p-glycoprotein.
  • Preferred agents are those which reverse multi-drug resistance, such as calcium channel blockers, reserpine, certain antimalarial drugs, cyclosporins, phenothiazines, tamoxifen and its metabolites, certain antibiotics, antisense oligonucleotides, and other compounds known to antagonize the activity of p-glycoprotein.
  • Useful antibodies include MRK-16, UIC2, 4E3, and their fragments.
  • antagonists of tissue factor are useful for the suppression of the development of immunity and of the immune response. Such antagonists include antibodies and antibody fragments to tissue factor, tissue factor antisense oligonucleotides, fragments of tissue factor, and compounds known to antagonize tissue factor such as dilazep and retinoic acid.
  • Suppression of the immune response is useful for the treatment of several diseases and conditions.
  • allergic reactions, graft-vs-host disease, transplant rejection, autoimmune diseases, progression of HIV infection, contact dermatitis, and food allergy are treatable by the methods and agents of the present invention.
  • the agents may be administered by appropriate routes including topical, parenteral, ophthalmic, nasal, pulmonary, etc., for delivery to the site of encounter of the dendritic cells with the antigen and to prevent their subsequent migration to the lymphatic vasculature.
  • certain methods and agents of the present invention may be used which enhance the migration of dendritic cells from the peripheral tissues to the lymphatic vessels. These methods and agents promote the development of immunity or of an immune response to a newly encountered antigen and enhance immunity or the immune response on re-encountering an antigen.
  • Agents useful in the practice of this aspect of the present invention are agonists of the dendritic cell membrane proteins p-glycoprotein and tissue factor. Examples of useful agents include bromocriptine, N-acetyl-leucine-leucine-tyrosine amide, and cytarabine for p-glycoprotein.
  • the agent is co- administered with an immunogen to enhance the development of an immune response to said immunogen, for example, when the immunogen is a vaccine.
  • methods for the identification of agents useful for the modulation of dendritic cell migration comprise the steps of first identifying an agent capable of interacting with the dendritic cell membrane proteins p- glycoprotein and tissue factor, followed by determining the extent of modulation of the migration of dendritic cells in vitro or in vivo by the agent. These methods identify agents useful for modulating the development of immunity or an immune response.
  • agents for the modulation of inflammation in a mammal are provided by an agent which is capable of enhancing the function of the monocyte membrane protein p-glycoprotein, and increasing the migration of inflammatory monocytic cells from the tissues.
  • Agents useful for the practice of this aspect of the invention include the aforementioned agonists of p-glycoprotein.
  • Increasing monocyte migration out of tissues is useful in the treatment of such inflammatory conditions as atherosclerosis, rheumatoid arthritis and granulomatous diseases.
  • methods for the identification of agents useful for the augmentation of monocyte migration out of tissues comprise the steps of first identifying an agent capable of enhancing the monocyte membrane protein p-glycoprotein, followed by determining the extent of augmentation of the migration of monocytes in vitro or in vivo by the agent. These methods identify agents useful for treating inflammatory conditions and diseases.
  • FIG. 1 A-B Effect of anti-MDR-1 monoclonal antibodies (mAbs) on transendothelial migration of mononuclear phagocytes.
  • mAbs monoclonal antibodies
  • Monocytes were allowed to migrate across endothelial monolayers with or without addition of anti-MDR-1 rnAb MRK16, or mAb to b 2 integrin (IB4) or CD31 (hec 7). Cultures were incubated for 1.5 hr.
  • monocytes were first allowed to accumulate beneath the endothelium in the absence of added mAb for 1.5 hours, followed by addition of mAbs (all IgG2a; MRK16 used as F(ab') 2 fragments) at the indicated concentrations; in some samples, monocytes were preincubated with MRK16 or isotype-matched control mAb hec 1 against cadherin 5 (Pre-MRK16 and Pre-Hec 1) before addition to the endothelium. After 48 hr, cultures were fixed for analysis.
  • mAbs all IgG2a; MRK16 used as F(ab') 2 fragments
  • FIG. 1 Effect of anti-MDR-1 mAb on emigration of DC and T lymphocytes from skin explants.
  • FIG. 3 A-C. Expression of MDR-1 in situ by DC.
  • A Epidermis derived from explants cultured with anti-MDR-1 mAb MRK16 were fixed and Cy3 -conjugated anti-mouse IgG was added to detect expression of MDR-1 (red). Addition of Cy3-labeled detection antibody to skin incubated in the presence of nonbinding control mAb (Heel) showed no staining (not shown).
  • B Immunostaining of same sample using FITC-conjugated anti-MHC II mAb (green) identified dendritic cells.
  • C Doubly-exposed frame to examine co-localization of p- glycoprotein and MHC II on dendritic cells (yellow). Bar is 10 ⁇ m.
  • FIG. 4 A-E Expression of functional MDR-1 by emigrated DC.
  • A-C MDR-1 expression in emigrated skin cells was examined by flow cytometry using double-staining with anti-MDR-1 mAb and the DC lineage marker MHC II (A, B) or the T lymphocyte lineage marker CD3 (C). Quadrants were marked based on the level of fluorescence intensity observed in samples stained with negative control mAbs.
  • D For studies measuring efflux,
  • FIG. 5 A-F Effect of verapamil on the efflux of the p-glycoprotein synthetic substrate 3,3'-diethyloxacarbocyanine iodide (DiOC 2 ) from dendritic cells.
  • Panels A and B show the fluorescence intensity of dendritic cells before loading with DiOC 2 . In these cells, the FL1 staining intensity (x-axis) is low.
  • Panels C-F show dendritic cells incubated under various conditions after loading with DiOC 2 , which fluoresces on the FL1 channel.
  • Panels B-F show cells after labeling for the cell surface marker MHC II (FL2 channel). Cell that shift 10 3 staining intensity on the FL2 channel are dendritic cells.
  • dendritic cells emigrated from skin were loaded with the dye and analyzed immediately for dye content
  • FIG. 6 A-D Retention of DC in the epidermis after treatment with MDR-1 antagonists.
  • n number of experiments in which each condition was examined. DC were counted from en face examinations of epidermal sheets in 16 to 20 high-power fields per experiment. Percent reduction in DC density was calculated by comparing the number of DC in cultured explants to the mean number present in a portion of the same skin sample before culture (typically 75 cells/field).
  • B-D Photomicrographs show the distribution of DC within the epidermis before culturing of explants (B), after three days of culture under control conditions (no mAb) (C), and after three days of culture in the presence of MRK16 (D). Bar is 20 ⁇ m.
  • FIG. 7 Effect of anti-MDR-1 mAb on the maturation of DC.
  • the levels of MHC II expressed by epidermal DC were analyzed in gated epidermal suspensions by flow cytometry before the onset of culture (Day 0) or after three days of culture in the absence of mAb or in the presence of MRK16.
  • Single cell suspensions of the epidermis were prepared by digestion with dispase followed by trypsin. Keratinocytes and other skin cells were excluded from the analysis by setting a gate to include only MHC II + cells.
  • Figure 8 Effect of anti-tissue factor monoclonal antibody (mAb) on emigration of dendritic cells (DC) and T lymphocytes from skin explants.
  • mAb monoclonal antibody
  • Explants of human skin were floated in culture medium without added mAb or in medium containing anti-tissue factor mAb VIC7 or control mAbs against cadherin 5 or carcinoembryonic antigen (CEA). After three days of incubation, DC and T lymphocytes that appeared in the culture medium were collected.
  • MHC II mAb for flow cytometry Figure shown was gated on MHC II + cells.
  • FIG. 10 A-B Effect of MRP antagonist MK 571 on emigration of DC from skin explants. Explants of human skin or explants of the dorsal aspect of mouse ear were floated
  • dendritic cells were collected and explants were transferred to fresh medium daily (with or
  • FIG 11 A-B Contact sensitization in MRP knock-out mice or after administration of MRP antagonist to wild-type mice.
  • the terms "immunity” or “development of immunity” are used generally to refer to the initial encounter of the immune system with an antigen and the development of a specific immune response to the antigen. This entails, in brief, the uptake of the antigen by antigen-presenting cells (APCs), especially dendritic cells (DC), processing of the antigen, and presentation of antigen peptides in a complex with MHC molecules, to T lymphocytes, with the subsequent formation of antigen- specific T lymphocytes, including memory, helper, and cytotoxic T lymphocytes, as well as antibody-producing B lymphocytes.
  • APCs antigen-presenting cells
  • DC dendritic cells
  • immune response is generally used herein to refer to the response of the immune system to a subsequent encounter with an antigen to which immunity has been previously established.
  • One aspect of this encounter is the uptake of the antigen by APCs, migration to draining lymphoid organs including lymph nodes and the spleen, and subsequent presentation to memory T lymphocytes that circulate in lymphoid tissues.
  • inflammation and "inflammatory response” refer to the acute or chronic response to a known or unknown antigen in which a particular general or local site within the body exhibits adverse sequelae of the accumulation of white blood cells, including monocytes, and their secreted mediators, producing a range of effects of varied intensities including pain, tenderness, edema, destruction of tissue, organ failure, asthma, and urticaria (hives).
  • atherosclerosis a chronic inflammatory disorder of the arterial wall, accumulation and retention of monocytes in the intimal tissue of the artery leads to lipid-laden plaque formation and danger of thrombosis.
  • the present invention relates to methods and agents for the modulation of the immune response involving the dendritic cell membrane proteins p-glycoprotein and tissue factor.
  • these proteins have been discovered to have an important physiological role in the migration of dendritic cells from the peripheral tissues, a location where antigen is encountered, to the lymphatic vessels, where interaction of the dendritic cell with T lymphocytes induces immunity or an immune response.
  • Manipulation of these proteins to antagonize or agonize their activities has been found to be useful for decreasing or increasing, respectively, the ability of the dendritic cell to migrate to the lymphatic vessels and thus modulate the development of immunity or an immune response to an antigen or antigens encountered by dendritic cells.
  • p-Glycoprotein also known as MDR-1
  • MDR-1 a large plasma membrane protein that functions as an ATP-driven chemotherapeutic drug efflux pump.
  • the endogenous substrate(s) for the p- glycoprotein transporter has not yet been identified, but based on structure-activity relationships of numerous compounds, are believed to include cationic, hydrophobic molecules with at least two planar rings and a molecular weight of 400-1500 (40).
  • Endogenous substrates also likely include modified phospholipids, such as phospholipids that are involved in cell signaling.
  • modified phospholipids such as phospholipids that are involved in cell signaling.
  • MDR multi-drug resistance
  • p-glycoprotein pumps out of the cell chemotherapeutic agents and thus renders cancer cells resistant to chemotherapy (36).
  • p-glycoprotein has been a target for pharmacologic intervention to disable the pump (36).
  • Numerous compounds have been found which antagonize the activity of the pump, and several are in use or in clinical development as adjunct therapy with cancer chemotherapeutic agents to block resistance. Prophylactic use has also been suggested to prevent the appearance of a drug resistant phenotype.
  • p-glycoprotein as defined herein embraces the MDR-1 gene product or the gene product(s) of structurally and functionally related transporters that mediate dendritic cell migration in humans and other mammals.
  • Methods and agents which have been found to effectively antagonize the activity of the p- glycoprotein protein are useful in the practice of the present invention for antagonizing p- glycoprotein and thus inhibiting dendritic cell migration and suppressing immunity or an immune response.
  • These methods and agents comprise several approaches, including but not limited to antibodies and fragments which bind to p-glycoprotein, compounds which reverse multi-drug resistance, and means to reduce the expression of p-glycoprotein. These methods and agents may be used singly or in combination.
  • administration may be targeted to a particular location of the body where the activity is desired, for example on or in an cutaneous lesion such as psoriasis or contact dermatitis, and delivery by aerosol or powder to the bronchi or lungs in the case of asthma.
  • Suppression or down-regulation of immunity and the immune response has utility in the prophylaxis and treatment of numerous diseases and conditions.
  • Methods and agents of the present invention are useful as prophylaxis against the exposure of an individual to a known immunogen or allergen against which an immune response would be highly undesirable.
  • acute exposure to a causative agent of contact dermatitis such as might occur in an industrial setting, for example, exposure to protein-modifying metals and their salts such as nickel and chromate as a result of a chemical spill, or release of a gaseous or airborne particulate allergen; a further example is topical or pulmonary exposure to urushiol, from contact with poison ivy or inhalation of smoke from burning foliage.
  • Immunity to accidental oral consumption of a potent immunogen may be blocked by the methods and agents of the present invention. An individual exposed under such conditions can prevent the delivery of the antigen to the lymph nodes by the methods and agents of the present invention.
  • immunogens that cause disease include pollen and other airborne allergens which cause allergic rhinitis and other seasonal allergic reactions, hay fever, allergic conjunctivitis; arthropod-borne antigens such as dist mites and insect secretions such as those that cause the reaction to mosquito bites; foods that cause allergies, etc.
  • pollen and other airborne allergens which cause allergic rhinitis and other seasonal allergic reactions, hay fever, allergic conjunctivitis
  • arthropod-borne antigens such as dist mites and insect secretions such as those that cause the reaction to mosquito bites
  • foods that cause allergies etc.
  • autoimmune diseases suspected antigens to which an immune response is responsible for the pathology have been identified; in others, the antigens are probable, and in others, they are uncertain.
  • as-yet identified immunogens responsible for pathological inflammatory conditions include food allergies of unknown cause, irritable bowel syndrome, rheumatoid arthritis, psoriasis and a large number of autoimmune diseases which are believed to be initiated and maintained by endogenous antigens.
  • means to block an immune response to transplanted antigens, in the form of acute rejection is provided. This may be used as an adjunct to immunosuppressive and other agents routinely used in transplantation.
  • the methods and agents of the present invention are not limited to, but are particularly useful in, the treatment of inflammatory conditions where the acute or chronic exposure to antigen occurs in the periphery, such as the skin, as well as the gut and the lungs.
  • one particular condition amendable to treatment by the methods and agents of the present invention is in the area of transplantation.
  • a critical role has been identified in the interaction of antigen-presenting cells, dendritic cells in particular, with T lymphocytes in initiating rejection. It is well established that dendritic cells mediate allograft rejection, since experimental techniques used to deplete allo grafts of endogenous dendritic cells do not give rise to subsequent rejection responses in recipients. However, it is not clinically feasible to deplete allografts of endogenous dendritic cells.
  • HIV Another disease particularly amenable to both prophylaxis treatment by the methods and agents of the present invention is HIV.
  • Transepithelial infection by HIV is believed to be mediated by dendritic cells, which become infected with the virus and carry the virus to lymph nodes where interactions between dendritic cells and T lymphocytes as described above lead to infection of T lymphocytes.
  • dendritic cells which become infected with the virus and carry the virus to lymph nodes where interactions between dendritic cells and T lymphocytes as described above lead to infection of T lymphocytes.
  • bone marrow-derived dendritic cells facilitate the creation of a population of CD 4+ T lymphocytes, which are a major reservoir of HIV infection.
  • Methods and agents of the present invention which block the migration of dendritic cells from peripheral sites, where dendritic cell HIV infection occurs, can interrupt the endogenous spread of infection; suppressing further dendritic cell migration inhibits the dendritic cell-mediated fostering of infected T lymphocyte populations.
  • antibodies or antibody fragments to p- glycoprotein may be administered to inhibit dendritic cell migration.
  • Antibodies may be made which bind to the extracellular portion of the p-glycoprotein molecule.
  • suitable antibodies include monoclonal antibodies MRK16 (24), 4E3 (23), and UIC2 (22).
  • Such antibodies include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library. Other fragments of such antibodies capable of binding to an epitope on the p-glycoprotein molecule are embraced herein.
  • the anti-p-glycoprotein antibodies of the invention may be cross reactive, e.g., they may recognize p-glycoprotein from different species. Polyclonal antibodies have greater likelihood of cross reactivity.
  • an antibody of the invention may be specific for a single form of p-glycoprotein, such as murine p-glycoprotein. Preferably, such an antibody is specific for human p-glycoprotein.
  • any technique that provides for the production of antibody molecules by continuous cell lines in culture may be used. These include but are not limited to the hybridoma technique originally developed by Kohler and Milstein [Nature 256:495-497
  • monoclonal antibodies can be produced in germ-free animals utilizing recent technology [PCT/US90/02545].
  • agents to inhibit dendritic cell migration are provided which are known to reverse multiple drug resistance.
  • Suitable agents may be selected from compounds that inhibit this drug transporter, including such non-limiting examples as calcium channel blockers such as verapamil, diltiazem, dihydroperidine, nifedipine, bepridil, and nicardipine; other cardiovascular drugs, including amiodarone, dipyridamole, and quinidine; antimalarial compounds such as quinine, quinacrine, and cinchonine; cephalosporin and other antibiotics such as cefoperazone, ceftriaxone, erythromycin, valinomycin, bafilomycin, and gramicidin; cyclosporins such as cyclosporine A and staurosporine; phenothiazines such as trifluoperazine, chlorpromazine and fluphenazine; hormones such as tamoxifen, N-des
  • PSC 833 is a cyclosporine analog with greater binding specificity for p-glycoprotein (36); it is 10-fold more potent than cyclosporine A and can reverse multi-drug resistance in vitro at concentrations of 0.5 to 2.0 ⁇ mol/L.
  • MK 571 is a substrate that antagonizes p-glycoprotein and murine multidrug resistance related protein (MRP), and is a particularly potent inhibitor of the latter.
  • MK 571 is known to be an antagonist of the leukotriene D 4 receptor (54), and as will be seen in the Examples below, has utility for the purposes described herein.
  • Other potent inhibitors of p-glycoprotein include S9788, rapamycin, MK 571, GF120918, and SR33557.
  • inhibition of p-glycoprotein in dendritic cells may be achieved by targeting gene expression with antisense oligonucleotides. This approach has been demonstrated feasible in vitro using mouse 3T3 fibroblasts (41).
  • tissue factor is a procoagulant protein present on the surface of numerous cell types, including endothelial cells, which line the vasculature, and monocytes, which circulate in blood. Increased expression of tissue factor by these cell types has been linked to many thrombotic disorders and pathologic states (see below with regard to increased expression).
  • monocyte membrane-associated tissue factor is not in an enzymatically active form that can initiate clotting; in order to become active, tissue factor must form an active complex with another of the clotting factors, Factor VII or its activated form, Factor Vila. This complex then leads to clot formation.
  • tissue factor may also be antagonized in order to inhibit dendritic cell mobility. This may be achieved by the use of antibodies and fragments against tissue factor.
  • a monoclonal antibody against tissue factor that inhibits migration of DC is VIC7.
  • Compounds known to inhibit tissue factor activity include the dilazep (42) and retinoic acid (43).
  • inhibition of tissue factor expression in dendritic cells may be achieved by targeting gene expression with antisense oligonucleotides to tissue factor (49).
  • a further strategy on interfering with tissue factor activity in order to suppress dendritic cell migration is through the use of purified, nonlipidated fragments of soluble recombinant human TF.
  • Enhancing the effectiveness of vaccination and other forms of immunotherapy is another feature of the present invention. This aspect is carried out using methods and agents which enhance or activate the dendritic cell membrane proteins p-glycoprotein and tissue factor.
  • Suitable activators of tissue factor include endotoxin (47), silver ion (47), and N,N'-dimethyl- ⁇ - ⁇ '-dipyridylium dichloride (48).
  • these agents are admixed with the immunogen to be used for vaccination.
  • a further utility of one aspect of the present invention is in the immunotherapeutic treatment of cancer.
  • Numerous studies and trials involve attempts to initiate or enhance an immune response in the patient toward the patient's own tumor. However, these regimens have provided little positive results, often because the patient is unable to mount an effective immune response to the tumor antigens. In this case, effective antigen presentation maybe suppressed.
  • the methods and agents of the present invention directed towards the enhancement of the immune response and increasing the effectiveness of vaccines has particular utility in the enhancement of therapeutic vaccines for cancer.
  • methods and agents may be used to increase dendritic cell migration in order to achieve an enhancement of the development of immunity or in a subsequent immune response to an antigen.
  • Enhanced development of immunity is particularly useful in enhancing the effectiveness of a vaccine, such as that for viruses such as poliomyelitis, rubella, measles, variola, and varicella, and especially poorly immunogenic immunogens such as influenza; bacteria such as Borrelia burgdorferi, the causative pathogen of Lyme disease, and other organisms including parasites such as malaria.
  • the invention herein is also useful in the various newer immunotherapeutic approaches to the prevention and control of other infectious diseases such as HIV and hepatitis, and immunotherapies of various cancers (infra).
  • potentially immunogenic components of the virion or tumor are prepared by various means and introduced into the patient in an attempt to develop immune recognition of the pathologic antigen(s). Often, the patient is immunocomprornised and cannot mount an effective immune response to the antigen.
  • One embodiment of the methods and agents of the present invention provide a means for increasing the delivery of antigen to the immune system by increasing or enhancing the migration of dendritic cells which have processed the antigen to the lymphatic vessels, where they may subsequently encounter T lymphocytes and induce cellular and humoral immunity.
  • the route of delivery of the agents of the present invention may be selected by one skilled in the art to provide the optimal contact with dendritic cells involved in the etiology of the condition to be treated or the route of exposure of the immunogen.
  • contact dermatitis, psoriasis, and other topical conditions may be treated by application of the agent of the present invention to the skin.
  • Allergic conjunctivitis may be treated by application of the agent to the eye.
  • Parenteral or other routes of administration which results in generalized delivery of the agent is also provided. Bronchiolar and pulmonary exposure may be achieved by aerosol and fine powder inhalation, respectively.
  • compositions of the above agents may be for administration for injection, or for oral, pulmonary, nasal or other forms of administration.
  • pharmaceutical compositions comprising effective amounts of a low molecular weight component or components, or derivative products, of the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
  • compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hylauronic acid may also be used.
  • buffer content e.g., Tris-HCl, acetate, phosphate
  • additives e.g., Tween 80, Polysorbate 80
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite
  • preservatives e.g.
  • compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the present proteins and derivatives. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, PA 18042) pages 1435-1712 which are herein incorporated by reference.
  • the compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form.
  • Contemplated for use herein are oral solid dosage forms, which are described generally in Remington's Pharmaceutical Sciences, 18th Ed.1990 (Mack Publishing Co. Easton PA 18042) at Chapter 89, which is herein incorporated by reference. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets.
  • liposomal or proteinoid encapsulation may be used to formulate the present compositions (as, for example, proteinoid microspheres reported in U.S. Patent No. 4,925,673).
  • Liposomal encapsulation may be used and the liposomes may be derivatized with various polymers (e.g., U.S. Patent No. 5,013,556).
  • U.S. Patent No. 5,013,556 A description of possible solid dosage forms for the therapeutic is given by Marshall, K. In: Modern Pharmaceutics Edited by G.S. Banker and C.T. Rhodes Chapter 10, 1979, herein incorporated by reference.
  • the formulation will include the component or components (or chemically modified forms thereof) and inert ingredients which allow for protection against the stomach environment, and release of the biologically active material in the intestine.
  • kits for the augmentation of the migration of monocytes are provided for the augmentation of the migration of monocytes, by enhancing the functioning of the monocyte membrane protein p-glycoprotein.
  • suitable agents and routes of delivery are as those described above in relation to modulating the same membrane protein on dendritic cells.
  • This aspect of the invention has utility in the treatment of various disorders, preferably chronic inflammatory conditions which are not necessarily, but may be, initiated or promulgated by antigens and antigen-specific immune cells such as cytotoxic T lymphocytes.
  • the development and progression of atherosclerotic lesions involves the progressive accumulation and retention of monocytes (which become tissue macrophages) and other cell types in lesions; the local inflammation mediated by their secretory products which attracts more pro-inflammatory cells, together with secretion of growth factors, is a pathophysiologic basis for vessel occlusion.
  • the methods and agents of the present invention directed to increasing monocyte migration has particular utility in preventing the retention of monocytes in inflammatory sites within the body, thus limiting the extent of inflammation.
  • Other examples of diseases and condition in which accumulation and retention of monocytes and resultant production of inflammatory mediators, growth factors and chemoattractants for additional inflammatory cells include rheumatoid arthritis and the granulomatous diseases.
  • various known methods for measuring the effect of compounds on p- glycoprotein activity may be adapted for use on dendritic cells.
  • dendritic cells may be isolated from skin explants and loaded with a dye known to be exported by functioning p-glycoprotein (28), such as 3,3'-diethyloxacarbocyanine iodide (DiOC 2 ).
  • Export of the dye may be measured in the absence and presence of compounds suspected of inhibiting or enhancing the activity of p-glycoprotein by decreasing or increasing, respectively, the pumping of the dye out of the cell.
  • agents useful for the modulation of dendritic cell migration may be identified by first identifying whether a candidate agent is capable of interacting with p-glycoprotein or tissue factor; and subsequently determining the extent of modulation of the agent on the migration of dendritic cells in vitro or in vivo.
  • the initial screen may be performed on cells which express p- glycoprotein, such as any one of numerous cancer cell lines.
  • the effect of the compound on the migration of dendritic cells may be performed as described below or that described in U.S. Patent 5,627,025, incorporated herein by reference.
  • This method employs human skin explants in culture to measure the effect of compounds on dendritic cell emigrating from the skin explant into the culture medium.
  • the methods disclosed herein are not limited to any particular method but are based upon the newly-identified role of p-glycoprotein and tissue factor on dendritic cells in cell migration.
  • assays may be performed to identify compounds which enhance migration of monocytes out of tissues.
  • migratory behavior of monocytes may be evaluated in an in vitro model of the blood vessel wall consisting of human umbilical vein endothelial cells (HUVEC) grown on type I collagen gels (see Example I, below).
  • HUVEC human umbilical vein endothelial cells
  • Human blood monocytes which express p-glycoprotein, transmigrate across the confluent endothelium and enter the collagenous substrate. The extent of migration is measured after exposure of the monocytes to the candidate. Other methods of measuring the migration of monocytes are known to the skilled artisan and are useful in the practice of the present invention.
  • a method for identifying compounds useful for modulating dendritic cell p-glycoprotein activity the following steps are carried out: i) loading isolated dendritic cells with a detectable substrate of the p- glycoprotein transporter activity; ii) exposing the loaded cells to an agent suspected of modulating p- glycoprotein activity; iii) measuring the rate of transport of the detectable substrate from the dendritic cells; and iv) comparing said rate to the rate of p-glycoprotein transporter activity determined of control dendritic cells not exposed to the agent.
  • an increase or decreased in the transport rate in the presence of the agent indicates the extent of activity of the agent in increasing or decreasing, respectively, p-glycoprotein activity of said dendritic cells.
  • compounds that are active in the above assay, either at increasing or decreasing p-glycoprotein activity can be additionally assays to determine if they are useful for modulating the migration of dendritic cells by determining the extent of modulation of the agent of the migration of dendritic cells in vitro or in vivo.
  • DC migration may be determined by any of several techniques, such as the emigration rate described in aforementioned U.S. Patent 5,627,025.
  • compounds may be evaluated directly in the emigration assay (7).
  • Activity may be evaluated in vivo by administration of the agent to an animal, followed by, for example, application of an antigen to the skin which would under normal circumstances induce immunity in the animal or an immune response.
  • the extent of the any reduction in the immune response elicited after administration of the agent is an indication of the extent of inhibition of dendritic cell migration.
  • compounds to be evaluated for the enhancement of the immune response may be evaluated in vivo by administering the agent parenterally or to the skin, for example, followed by application of an immunogen. Any resulting enhancement of the immune response as compared with control animals indicates positive activity in enhancing the immune response.
  • PBMC peripheral blood mononuclear cells
  • Skin Cultures Human split-thickness skin was obtained from the New York Firefighter's Skin Bank (New York Hospital-Cornell Medical Center) from cadavers within 24 hr of death, or from patients undergoing plastic surgery, and was authorized for use in research.
  • dermatomes were approximately 300-mm thick, including both epidermis (about 100-mn ⁇ ) and a portion of the dermis.
  • Skin was prepared, cultured, and emigrated cells were quantitated as previously described (7). Each explant was trimmed to 400-mm 2 and floated in 3 to 6 ml culture medium. When used, mAbs or verapamil (Sigma) were added to the culture medium at the onset of culture, and cultures were incubated undisturbed until the indicated day of analysis. Verapamil was prepared as a concentrated stock in methanol. Final methanol concentration in cultures was 0.03% (vol/vol).
  • Immunoblots Emigrated DC were purified by negative selection: anti-CD3 mAb was incubated with emigrated cells, and T lymphocytes were removed using anti-mouse IgG-conjugated magnetic beads (Dynal). The purity of the resulting population was verified by flow cytometric evaluation after staining with PE-conjugated anti-MHC II (Becton
  • Microsomal membranes from 5 million thus purified DC, 25 million PBMC, or 5 million HUVEC were prepared as described (13), subjected to SDS-PAGE (4-12% gradient gel) under reducing conditions, and electroblotted onto a nitrocellulose membrane.
  • the membrane was probed with 5 mg/ml C219 anti-MDR-1 mAb (Centocor) and visualized using peroxidase-conjugated anti-mouse IgG, followed by ECL substrate (Amersham).
  • Emigrated cells were incubated in RPMI-1640 containing 20 ng/ml DiOC 2 (Molecular Probes) for 15 min. at 37 °C, washed twice in ice cold medium, resuspended in 10% fetal bovine serum/RPMI-1640 containing no additives or with addition of 10 mg/ml UIC2 mAb (Coulter). After 90 min. of incubation at 37 °C, cells were washed and immediately placed on ice for labeling with PE-conjugated anti-MHC II mAb and analysis by flow cytometry.
  • EXAMPLE 1 Role of MDR-1 in basal-to-apical transendothelial migration of mononuclear phagocytes.
  • the present inventors were drawn to investigate the role of p-glycoprotein in dendritic cell migration by a set of observations with blood monocytes, now known to be a progenitor of DC when appropriately stimulated with cytokines (15-19).
  • the migratory behavior of monocytes was examined in an in vitro model of the blood vessel wall consisting of human umbilical vein endothelial cells (HUVEC) grown on type I collagen gels (10, 11).
  • Human blood monocytes which express MDR-1 (20, and data not shown), transmigrate across the confluent endothelium and enter the collagenous substrate.
  • MRK16 used here as F(ab') 2 fragments, was the most potent blocking mAb, exhibiting maximal levels of inhibition using as little as 0.5 to 1.0 mg/ml.
  • Preincubation of monocytes with MRK16, and subsequent removal of unbound mAb before addition of these cells to the endothelium blocked reverse transmigration as well as when the mAb was present continuously during the assay (Pre-MRK16, Fig. IB). No other mAbs screened inhibited reverse transmigration, except one against tissue factor.
  • EXAMPLE 2 Role of MDR-1 in mobilization of DC and T lymphocytes from skin.
  • Nerapamil a drug that antagonizes MDR-1 transport (26), reduced DC and T lymphocyte accumulation in the culture medium by 52 ⁇ 19% at 10 mg/ml (20 mM) (Fig. 2 A).
  • the anti-MDR-1 mAb UIC2 also blocked migration, by 75 ⁇ 2% when used at 2 mg/ml (Fig. 2A).
  • An isotype matched control mAb against cadherin 5 (Hec 1) (11) that does not react with DC or T cells had no effect.
  • T lymphocytes are known to express MDR-1 (14, 20, 27), but its expression by DC has not been reported previously. Immunostaining for MDR-1 was observed on DC in the epidermis (Fig. 3A and C). The same cells also stained positively for the DC marker MHC II (Fig. 3B and C). No other cell types in the skin, such as keratinocytes or fibroblasts, showed positive staining for MDR-1 in these experiments.
  • skin was cultured in the presence of MRK16 for two days, as for migration analysis. Then staining was carried out on tangential sections prepared from snap-frozen skin, applying only anti-mouse Cy3-conjugated detection antibody.
  • MDR-1 MDR-1, DiOC 2 .
  • DC transported this substrate into the surrounding medium, showing a log decrease in fluorescence intensity (Fig. 4D), and this efflux was inhibited by anti-MDR-1 mAb UIC2 (Fig. 4D).
  • mAb C219 Another mAb that reacts with MDR-1.
  • EXAMPLE 4 Effect of Verapamil on the DiOC 2 Efflux from Dendritic Cells
  • Figure 5 further documents that functional p-glycoprotein is expressed by dendritic cells and that p-glycoprotein-mediated transport can be blocked by agents, particularly verapamil and a monoclonal antibody against p-glycoprotein, that are known to inhibit p-glycoprotein transport activity.
  • agents particularly verapamil and a monoclonal antibody against p-glycoprotein, that are known to inhibit p-glycoprotein transport activity.
  • dendritic cells were loaded with the p-glycoprotein synthetic substrate 3,3'-diethyloxacarbocyanine iodide (DiOC 2 ), and flow cytometry performed as described in Example 3.
  • Example 5 Effect of MDR-1 antagonists on maturation and retention of DC in epidermis.
  • epidermal and dermal sheets prepared from cultured skin explants were stained for MHC II (29, 30).
  • Fig. 6A, B the number of DC remaining in the epidermis after three days of culture under control conditions was decreased by 56% (Fig. 6A, C).
  • Fig. 6A, D the number of DC remaining in the epidermis after three days of culture under control conditions was decreased by 56%
  • Fig. 6A, C In explants cultured in the presence of MRK16 (Fig. 6A, D), UIC2 (Fig. 6A), or verapamil (Fig. 6A), a more limited reduction in DC density of 13%, 11%, and 25%, respectively, were observed.
  • antagonism of MDR-1 results in retention of DC in the epidermis.
  • Explants of human skin were floated in culture medium without added monoclonal antibody or in medium containing anti-tissue factor monoclonal antibody VIC7 or control antibodies against cadherin 5 or carcinoembryonic antigen (CEA). After three days of incubation, DC and T lymphocytes that appeared in the culture medium were collected. Each experiment was conducted with 3-4 replicates per parameter tested. The number of emigrated cells recovered from individual control explants was typically 5 x 10 5 . To compare data from different experiments, the mean number of emigrated cells in the absence of added monoclonal antibody in each experiment was set equal to 1.0 and relative values were obtained for the remaining data. Cumulative results from three independent experiments are shown in Figure 8. These experiments show that monoclonal antibody to tissue factor reduces the emigration of cells from skin explants by about 50%.
  • mouse skin explants derived from
  • DCs Dendritic cells
  • MRP murine multidrug resistance related protein
  • glycoprotein-related transporter was further evident from the observation that MRP knock ⁇
  • mice failed to efflux the fluorescent substrate Fluo-3 (Fig. 9A, right panel).
  • the pharmacologic compound MK 571 is a substrate that antagonizes p-glycoprotein and
  • MRP but is a particularly potent inhibitor of the latter (52).
  • MK 571 was added to
  • MRP knock-out mice and age-matched wild-type mice were employed in a contact
  • Dendritic cells were analyzed for their transport of the contact sensitizer FITC to lymph
  • mice was reduced by 87% in the absence of MRP expression (Fig. IIA).
  • MK 571 was administered i.v. (50 mg / kg body weight) four

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Abstract

L'invention concerne des procédés et des agents permettant de stimuler et de diminuer la migration de cellules dendritiques de manière à supprimer ou à accroître le développement de l'immunité et la réponse immunitaire au moyen d'une modulation de la p-glycoprotéine (MDR-1) et de la thromboplastine tissulaire des protéines membranaires des cellules dendritiques. Les agents suppresseurs de migration sont utiles pour le traitement des maladies à médiation immunologique et des maladies inflammatoires telles que les rejet de greffes, les dermatites de contact, les allergies saisonnières, l'asthme, et les allergies alimentaires. Les agents qui stimulent la migration sont utiles pour accroître l'efficacité des vaccins. L'invention concerne également des agents qui stimulent la migration des monocytes, et sont utiles pour le traitement des maladies inflammatoires chroniques. L'invention concerne également des procédés permettant d'identifier des agents utiles en mesurant l'effet produit par des agents modulant l'activité p-glycoprotéine et l'activité du facteur tissulaire sur la migration des cellules dendritiques, ainsi que l'effet de ces agents sur la migration des monocytes.
PCT/US1999/012681 1998-06-04 1999-06-04 Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques WO1999062537A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028543A1 (fr) * 1999-10-15 2001-04-26 Mayo Foundation For Medical Education And Research Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d)
WO2001035946A3 (fr) * 1999-11-15 2002-01-10 New Millennium Pharmaceutical Administration intranasale de raloxifene et de tamoxifene
WO2002100406A1 (fr) * 2001-06-12 2002-12-19 Enzo Leone Utilisation d'yohimbine dans la preparation de medicaments actifs au niveau immunobiologique
AU2002334870B8 (en) * 2001-10-05 2003-04-22 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
WO2004050706A2 (fr) * 2002-12-03 2004-06-17 Medical Research Council Lymphocytes t regulateurs
EP1534256A2 (fr) * 2002-06-17 2005-06-01 Philadelphia Health and Education Corporation Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
WO2004112794A3 (fr) * 2003-06-18 2005-06-16 Novartis Ag Nouvelle utilisation de derives de staurosporine
EP1647256A1 (fr) * 2003-07-09 2006-04-19 Oncorex, Inc. Composition activant la capacite de filtration de cellules dentritiques et activateur immunitaire
WO2006134022A1 (fr) * 2005-06-17 2006-12-21 Boehringer Ingelheim International Gmbh Inhibiteurs mrp iv pour le traitement de maladies respiratoires
EP1779848A1 (fr) * 2005-10-28 2007-05-02 Nikem Research S.R.L. Inhibiteurs de la V-ATPase pour le traitement des maladies inflammatoires et autoimmunes
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders
WO2015118167A1 (fr) * 2014-02-10 2015-08-13 Institut Curie Utilisation de modulateurs de mcoln-1 pour réguler la migration cellulaire
CN112074596A (zh) * 2018-02-09 2020-12-11 亥姆霍兹慕尼黑-德国健康与环境研究中心(有限公司) 监测疤痕形成的装置和方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980898A (en) 1996-11-14 1999-11-09 The United States Of America As Represented By The U.S. Army Medical Research & Material Command Adjuvant for transcutaneous immunization
US20060002949A1 (en) 1996-11-14 2006-01-05 Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. Transcutaneous immunization without heterologous adjuvant
US6797276B1 (en) 1996-11-14 2004-09-28 The United States Of America As Represented By The Secretary Of The Army Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response
CA2437899C (fr) 2001-02-13 2012-05-15 Gregory M. Glenn Vaccin pour immunisation transcutanee contre la diarrhee du voyageur causee par l'etec

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001645A1 (fr) * 1994-07-11 1996-01-25 Peptech(Uk) Limited Utilisation de composes peptidiques de muramyle
WO1997012633A1 (fr) * 1995-10-04 1997-04-10 Immunex Corporation Facteur de stimulation de cellules dendritiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001645A1 (fr) * 1994-07-11 1996-01-25 Peptech(Uk) Limited Utilisation de composes peptidiques de muramyle
WO1997012633A1 (fr) * 1995-10-04 1997-04-10 Immunex Corporation Facteur de stimulation de cellules dendritiques

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CUMBERBATCH M ET AL: "Tumour necrosis factor-alpha is required for accumulation of dendritic cells in draining lymph nodes and for optimal contact sensitization.", IMMUNOLOGY, (1995 JAN) 84 (1) 31-5., XP002112754 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; LARSEN C P ET AL: "Migration and maturation of Langerhans cells in skin transplants and explants.", XP002112758, retrieved from STN Database accession no. 91037811 *
JOURNAL OF EXPERIMENTAL MEDICINE, (1990 NOV 1) 172 (5) 1483-93. *
LAVIE Y. ET AL.: "Agents that reverse multidrug resistance, Tamoxifen, Verapamil, and Cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells", J. BIOL.CHEM., vol. 272, no. 3, 17 January 1997 (1997-01-17), pages 1682 - 87, XP002112756 *
MA J ET AL: "In vivo treatment with anti-ICAM-1 and anti-LFA-1 antibodies inhibits contact sensitization-induced migration of epidermal Langerhans cells to regional lymph nodes.", CELLULAR IMMUNOLOGY, (1994 OCT 15) 158 (2) 389-99., XP002112755 *
RANDOLPH G J ET AL: "A physiologic function for p - glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, (1998 JUN 9) 95 (12) 6924-9., XP002112757 *
RANDOLPH G J ET AL: "Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro.", BLOOD, (1998 DEC 1) 92 (11) 4167-77., XP002112753 *

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WO2001035946A3 (fr) * 1999-11-15 2002-01-10 New Millennium Pharmaceutical Administration intranasale de raloxifene et de tamoxifene
WO2002100406A1 (fr) * 2001-06-12 2002-12-19 Enzo Leone Utilisation d'yohimbine dans la preparation de medicaments actifs au niveau immunobiologique
AU2002334870B8 (en) * 2001-10-05 2003-04-22 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US7915265B2 (en) 2001-10-05 2011-03-29 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
AU2002334870B2 (en) * 2001-10-05 2007-10-04 Zalicus Inc. Combinations for the treatment of immunoinflammatory disorders
US7253155B2 (en) * 2001-10-05 2007-08-07 Combinatorx, Inc. Combinations for the treatment of immunoinflammatory disorders
EP1534256A4 (fr) * 2002-06-17 2007-06-20 Philadelphia Health & Educatio Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
EP1534256A2 (fr) * 2002-06-17 2005-06-01 Philadelphia Health and Education Corporation Immunomodulation et action sur des processus cellulaires relatifs aux recepteurs de la famille de la serotonine et la barriere hemato-encephalique
WO2004050706A2 (fr) * 2002-12-03 2004-06-17 Medical Research Council Lymphocytes t regulateurs
WO2004050706A3 (fr) * 2002-12-03 2004-09-16 Medical Res Council Lymphocytes t regulateurs
AU2004248909B2 (en) * 2003-06-18 2008-05-08 Novartis Ag New pharmaceutical uses of staurosporine derivatives
WO2004112794A3 (fr) * 2003-06-18 2005-06-16 Novartis Ag Nouvelle utilisation de derives de staurosporine
US8575146B2 (en) 2003-06-18 2013-11-05 Novartis Ag Pharmaceutical uses of staurosporine derivatives
JP2012144572A (ja) * 2003-06-18 2012-08-02 Novartis Ag スタウロスポリン誘導体の新規医薬的使用
JP2006527727A (ja) * 2003-06-18 2006-12-07 ノバルティス アクチエンゲゼルシャフト スタウロスポリン誘導体の新規医薬的使用
EP1647256A4 (fr) * 2003-07-09 2007-10-31 Oncorex Inc Composition activant la capacite de filtration de cellules dentritiques et activateur immunitaire
EP1647256A1 (fr) * 2003-07-09 2006-04-19 Oncorex, Inc. Composition activant la capacite de filtration de cellules dentritiques et activateur immunitaire
US8080553B2 (en) 2003-10-15 2011-12-20 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders
WO2006134022A1 (fr) * 2005-06-17 2006-12-21 Boehringer Ingelheim International Gmbh Inhibiteurs mrp iv pour le traitement de maladies respiratoires
EP1779848A1 (fr) * 2005-10-28 2007-05-02 Nikem Research S.R.L. Inhibiteurs de la V-ATPase pour le traitement des maladies inflammatoires et autoimmunes
WO2015118167A1 (fr) * 2014-02-10 2015-08-13 Institut Curie Utilisation de modulateurs de mcoln-1 pour réguler la migration cellulaire
JP2017510291A (ja) * 2014-02-10 2017-04-13 アンスティテュ・キュリＩｎｓｔｉｔｕｔ Ｃｕｒｉｅ 細胞遊走を調節するためのＭｃｏｌｎ−１モジュレータの使用
US10100313B2 (en) 2014-02-10 2018-10-16 Institut Curie Use of Mcoln-1 modulators to regulate cell migration
EP3705570A1 (fr) * 2014-02-10 2020-09-09 Institut Curie Utilisation de modulateurs mcoln-1 afin de réguler la migration cellulaire
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